Disease mechanisms

Mission

The research group clarifies the disease mechanisms in inherited neurodegenerative diseases. Both cell biological methods and mouse models are utilized to reach the goal.

Research

The goal of the research group is to clarify the disease mechanisms in four neurodegenerative disorders: Aspartylglucosaminuria (AGU), infantile neuronal ceroid lipofuscinosis (INCL), Batten disease and vLINCL. These disorders are caused by defects in single genes and the aim is to identify the disturbances in cellular and tissue metabolism caused by these defects. To date we have elucidated the intracellular trafficking and function of the disease proteins and the data has implicated that at least two of these proteins have specific transport mechanisms in neuronal cells. This could partially explain the fact that these diseases are manifested in the central nervous system. Additionally, we have produced knockout mouse models for three of the diseases (AGU, INCL and vLINCL) and have obtained the Batten disease knockout mouse through collaboration. We have used the mouse models to analyze the tissue pathology in the central nervous system and gene therapy has so far been utilized to treat the neuronal pathology of AGU. An important goal is to integrate the new bioinformatic tools and microarray technologies to the studies of disease mechanisms. The development of research tools in these diseases will set the basis to study the disease mechanisms in common diseases which is one of the main missions of the National Public Health Institute. The research group belongs to the Center of Excellence in Disease Mechanisms funded by the Academy of Finland.

Research group:

Jalanko Anu, dosentti
Antila Kaija, laboratoriohoitaja
Kyttälä Aija, FT, dosentti
Lyly Annina, FM
Maaranen Elina, fil.yo
von Schantz-Fant Carina, FM
Schmiedt, Mia
Tervaniemi, Mari
Toivola Auli, laboratoriohoitaja
Uusi-Rauva Kristiina, fil.yo

Core-unit

Kaiharju Essi, bioanalyst

Most important publications

Ahtiainen L, Kolikova J, Mutka AL, Luiro K, Gentile M, Ikonen E, Khiroug L, Jalanko A, Kopra O. Palmitoyl protein thioesterase 1 (Ppt1)-deficient mouse neurons show alterations in cholesterol metabolism and calcium homeostasis prior to synaptic dysfunction. (2007) Neurobiol. Dis. Jun 23.

Lyly A, von Schantz C, Salonen T, Kopra O, Saarela J, Jauhiainen M, Kyttälä A, Jalanko A. Glycosylation, transport and complex formation of palmitoyl protein thioesterase 1 (PPT1) - distinct characteristics in neurons. (2007) BMC Cell Biol. Jun 12;8:22.

Luiro K, Kopra O, Blom T, Gentile M, Mitchison HM, Hovatta I, Törnquist K, Jalanko A. Batten disease (JNCL) is linked to disturbances in mitochondrial, cytoskeletal, and synaptic compartments.(2006) J Neurosci Res. 84:1124-38.

Ahtiainen L, Luiro K, Kauppi M, Tyynelä J, Kopra O, Jalanko A. Palmitoyl protein thioesterase 1 (PPT1) deficiency causes endocytic defects connected to abnormal saposin processing. (2006) Exp Cell Res. 312:1540-53.

Jalanko A, Vesa J, Manninen T, von Schantz C, Minye H, Fabritius AL, Salonen T, Rapola J, Gentile M, Kopra O, Peltonen L. Mice with Ppt1Deltaex4 mutation replicate the INCL phenotype and show an inflammation-associated loss of interneurons. (2005) Neurobiol Dis. 18:226-41.

Kopra O, Vesa J, von Schantz C, Manninen T, Minye H, Fabritius AL, Rapola J, van Diggelen OP, Saarela J, Jalanko A, Peltonen L. A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging. (2004) Hum. Mol. Genet. 13:2893-906.

Luiro, K, Yliannala, K, Ahtiainen, L, Maunu, H, Järvelä, I, Kyttälä, A, Jalanko, A. Interconnections of CLN3, Hook1 and Rab proteins link Batten disease to defects in the endocytic pathway. (2004) Hum. Mol. Genet. 13:3017-3027.

Luiro, K., Kopra, O., Lehtovirta, M., Jalanko, A. CLN3 protein is targeted to neuronal synapses but excluded from synaptic vesicles: New clues to Batten disease. (2001) Hum. Mol. Genet. 10:2123-2131.

Lehtovirta, M., Kyttälä, A., Eskelinen, E-L., Hess, M., Heinonen, O., Jalanko, A. Palmitoyl protein thioesterase (PPT) localizes into synaptosomes and synaptic vesicles in neurons: Implications for infantile neuronal ceroid lipofuscinosis (INCL). (2001) Hum. Mol. Genet. 10:69-75.

Järvelä, I., Lehtovirta, M., Tikkanen, R., Kyttälä, A., Jalanko, A. Defective intracellular trans port of CLN3 is the molecular basis of Batten disease (JNCL). (1999) Hum. Mol. Genet. 8:1091-1098.

Jalanko, A., Tenhunen, K., McKinney, C.E., LaMarca, M.E., Rapola, J., Autti, T., Joensuu, R., Manninen, T., Sipilä, I., Ikonen, S., Riekkinen, P. Jr., Ginns, E.I., Peltonen, L. Mice with aspartylglucosaminuria mutation similar to humans replicate the pathophysiology in patients. (1998) Hum. Mol. Genet. 7: 265-272.

Ph.D. Dissertations

Laura Ahtiainen - Unravelling Molecular and Cellular Disease Mechanisms in Infantile Neuronal Ceroid Lipofuscinosis (INCL). University of Helsinki, 2007. E-thesis

Kaisu Luiro - Molecular and cellular mechanisms behind juvenile neuronal ceroid lipofuscinosis (JNCL, Batten disease). University of Helsinki, 2006. E-thesis

Liina Lonka - Neuronal ceroid lipofuscinosis CLN8 – from gene to protein. University of Helsinki, 2004. (Supervised with Prof. Anna-Elina Lehesjoki).E-thesis

Tarja Salonen - Molecular and cellular biology of infantile neuronal ceroid lipofuscinosis (INCL). Publication of the National Public Health Institute, University of Helsinki, 2001. E-thesis

Kai Tenhunen - Mouse aspartylglucosaminidase gene and mouse model for aspartylglucosaminuria. Publication of the National Public Health Institute, University of Helsinki, 1998. (Supervised with Prof. Leena Palotie).

Annukka Uusitalo - Aspartylglucosaminuria: Disease pathogenesis, developmental expression and regulation of the aspartylglucosaminidase gene. Publication of the National Public Health Institute, University of Helsinki, 1998. (Supervised with Prof. Leena Palotie).

Minna Peltola-Laine - Aspartylglucosaminuria (AGU): Lysosomal targeting of AGA, the cellular consequences of mutations and an attempt at gene therapy in the AGU mouse. Publication of the National Public Health Institute, University of Helsinki, 1998. (Supervised with Prof. Leena Palotie).

Aija Riikonen-Kyttälä - Intracellular maturation of aspartylglucosaminidase. Publication of the National Public Health Institute, University of Helsinki, 1996. (Supervised with Prof. Leena Palotie).

Nina Enomaa - Aspartylglucosaminuria: molecular pathogenesis and in vitro correction of the enzyme defect. Publication of the National Public Health Institute, University of Helsinki, 1994. (Supervised with Prof. Leena Palotie).

Additional information

Docent Anu Jalanko
e-mail: firstname.